Risk Factors for Venous Thromboembolism in Metastatic Colon Cancer Patients in the Contemporary Treatment Era: A SEER-Medicare Data Analysis

Background:The relationship between metastatic colorectal cancer (CRC) and venous thromboembolism (VTE) is not well defined in the modern treatment era. Previous population-based studies date back to a period marked by inpatient intravenous heparin therapy and inferior survival due to paucity of therapeutic anti-cancer options, and before the advent of newer therapies including oxaliplatin, irinotecan, and anti-angiogenic treatment with bevacizumab. The objectives of this retrospective study were to examine the impact of multiple putative risk factors on VTE incidence in a large representative modern cohort of older patients with metastatic CRC.

Methods:We performed a retrospective analysis of SEER-Medicare data on elderly patients with metastatic CRC diagnosed in 2004-2011. VTE and associated risk factors were analyzed using multivariate Cox proportional hazards models adjusted for sex, age at diagnosis, race, ethnicity, tumor anatomy (left/right/unknown), calendar year of diagnosis, Charlson comorbidity score, location of SEER registry and urban residence, with time-varying covariates for use of cancer therapies.

Results:Of 339,778 records, 11,086 metastatic colon cancer cases were identified. 1,338 cases had VTE with a cumulative incidence of 13% at 1 year and 19% at 3 years. The mean age was 77.9 years (range 65-106). 49.7% were women and 83.5% white. 60.5% had a Charlson comorbidity score of zero at diagnosis; 6% had scores of 6-18.

Significant predictors of VTE included female sex (Hazard Ratio (HR) 1.22; 95% Confidence Interval (CI) 1.10, 1.36; P<0.001), younger age at diagnosis (HR 1.25 per decade of age; CI 1.15, 1.37; P<0.001), urban residence (HR 1.20; CI 1.03, 1.40; P=0.02), right sided colon cancers (HR 1.19; CI, 1.06, 1.33 P=0.003), and current use of 5-fluorouracil (HR 1.33; CI 1.04, 1.70; P=0.02). The risk of VTE was significantly reduced when on bevacizumab (HR 0.77; CI 0.63, 0.93; P=.006), or irinotecan therapy (HR 0.59; CI 0.47, 0.75; P<0.001) and in those with more comorbid conditions (HR 0.97 per point of Charlson score; CI 0.935, 0.998; P=0.04).

Conclusion: The higher incidence of VTE seen in right sided colon cancers may be related to biologically aggressive tumors associated with poor survival as reported in recent studies. The lower risk of VTE in older, sicker patients was unexpected and may reflect the effect of competing mortality. In this large contemporary cohort, anti-angiogenic therapy was not associated with a higher risk of VTE; the apparent protective effects of bevacizumab and irinotecan may represent treatment assignment bias.